We have recently discovered an unexpected connection between a critical lung cancer gene termed thyroid transcription factor 1 (TTF-1 also known as NKX2-1) and cholesterol metabolism. By searching for downstream target microRNAs of TTF-1, we found that TTF-1 upregulates miR-33a which is known to be critical for cholesterol regulation by suppressing ATP-binding cassette transporter 1 (ABCA1) and its associated cholesterol efflux function. Thus, we set out to demonstrate that a higher TTF-1 expression would presumably inhibit cholesterol efflux and raise intracellular cholesterol level. Surprisingly in our preliminary studies we found that raising TTF-1 expression actually lowers intracellular cholesterol level, which we believe is attributed to our discovery that TTF-1 directly transactivates ABCA1. In view of the fact that cholesterol is essential for cell viability, we surmised that lung cancer cells primed with a TTF-1-driven decrease of cholesterol would be sensitized to cholesterol biosynthesis inhibitors. Indeed, enforced expression of TTF-1 in human lung cancer cells enhanced cellular sensitivity to statins, a frequently prescribed medication to lower systemic cholesterol. Under Aim 1, we plan to comprehensively characterize the functional requirement of ABCA1 for the enhanced statin sensitivity of cells with TTF-1 overexpression. Subsequently, under Aim 2 we wish to use both orthotopic and anonymized patient-derived lung cancer model systems to test the efficacy of statins against TTF-1+ lung adenocarcinomas. Given the fact that pathologists routinely interrogate human lung cancers for TTF-1 immunopositivity to guide diagnosis and the prevalent use of statins, the outcome of this study will inspire translational and clinical research to improve lung cancer management.